Aqueous viscous compositions, whether clear or not, for making soft or hard capsules, and method for making films for such capsules

ABSTRACT

The invention concerns aqueous viscous compositions, whether clear or not, for making soft or hard capsules, and method for making films for such capsules (gelled capsules). Said compositions are in particular characterised in that they contain a single gelling agent consisting of a carrageenan, preferably an Iota carrageenan, whereof the concentration in the medium is higher than 5% of the medium which can be aqueous and oily. The invention also concerns a method for making films for such capsules which consists in dehydrating said films by oven drying or lyophilisation. The invention is applicable in pharmaceutics, cosmetics and dietetics.

This is a 371 of PCT/FR98/01744 filed Aug. 5, 1998.

BACKGROUND OF THE INVENTION

Field of Invention

The present invention relates to the field of pharmaceutics, cosmeticsand dietetics and has for objective to make pure carrageenan films forthe manufacturing of hard and soft capsules or gelled capsules as wellas a method for making the said film and soft capsules.

Discussion of the Background

Currently, the shell of both gelled capsules and capsules comprisesgelatin as a base used either pure (for gelled capsules) or incombination with different substances, glycerine, sorbitol, etc, in thecase of soft capsules.

However, due to major problems arising from the origin of gelatin, whichcomes mainly from bovine bones, the disease called “mad cow disease” orBSE (Bovin Spongiform Encephalitis) makes it crucial to find asubstitute for such product.

Quite a number of products having gelifying characteristics or formingpseudo-colloidal solutions have been tested such as starch, cellulose,and hydrocolloids such as alginate, pectin, xanthane gum, etc.

The results obtained have not been conclusive in the case of hard andsoft capsules, apart from the cellulosic by-products such ashydroxypropylmethyl cellulose for the manufacturing of gelled capsules.

Quite an amount of work has been carried out and has led to patents.Among these, the Japanese patents No. 09025228, No. 62289530, No.61010508 and U.S. Pat. Nos. 5,342,626 mention carrageenans as asubstitute for gelatin. But, in every case, they are always combinedwith another gelling agent such as mannans, galactomannans, agar, etc,and in fairly low concentrations in the order of 1 to 2%. The U.S. Pat.No. 5,342,626 and Japanese patent No 60012943 only mention Kappacarrageenans (K-carrageenans) even though it is known that filmsobtained from this type of carrageenans present an important power ofretraction: synerese phenomenon working against the manufacturing ofhard and soft capsules. Furthermore, this type of carrageenans does notenable to obtain a highly concentrated fluid solution in hot work as incold work.

SUMMARY OF THE INVENTION

The aim of the present invention is to make the substitution of film forthe hard and soft capsules with a shell based from a product of whollyvegetal origin which is much used in the food industry field, thecarrageenans used pure as the one and single gelling agent of thecomposition of the shell with a concentration higher than 5% in solutionin the medium. It is based on the fact that carrageenans heated between50° C. and 100° C. have, when cooling, the characteristic to gelify andproduce more or less breakable films depending on the type ofcarrageenans used. The Iota (ι) type preferally adopted in the presentinvention does not present the synerese phenomenon and leads to filmspresenting a certain elasticity necessary to the manufacturing of softcapsules. The addition of a certain number of substances leads to thefilms obtained presenting similar physical characteristics to those ofgelatin on the level of elasticity, thickness of films, time ofdisintegration, welding of films, as well as their appearance:transparent films, that can be coloured and cut to variable size.

The carrageenans have been known for over 600 years in the medical fieldand in foods in particular for their original characteristic whichconsisted in gelifying milk by a simple heating process. These arepolysaccharides, polymers of galactose which are more or less sulfated.

The carrageenans that can be used in the present invention are,generally, extracts from different algae: Chondrus crispus, Gigartinastellata, Gigartina acicularis, Gigartina skottsbergii, Gigartinapistillata, Gigartina chamissoi, Iridea, Eucheuma cottoni, Eucheumaspinosum.

The extracting method implemented leads to different types ofcarrageenans of which the basic frame is a chain of D-galactosesalternately linked in α—(1-3) and β—(1-4).

The different qualities are due to the quantity and to the position ofthe sulfates and the presence or not of a bridge 3, 6 anhydride on thegalactose linked in 1 and 4.

DETAILED DESCRIPTION OF THE INVENTION

The different types of carrageenans that can be used in the presentinvention are

Iota (ι) carrageenans;

Lambda (λ) carrageenans;

Mu (μ) carrageenans;

Nu (ν) carrageenans;

the last two being in lower quantity in the wild.

The proportions of the different combinations vary according to thealgae species.

The different carrageenans differ from one another by the proportion ofsulfate groups present on the basic frame of the molecule.

The Lambda (λ) shapes present several sulfate groups in comparison withthe Kappa (κ) shapes. The Iota (ι) shapes are intermediary.

The Mu (μ) and Nu (ν) shapes are in lower quantity and are considered asimpureties lowering the gelling effect of the Iota (ι) and Kappa (κ)shapes.

The Lambda (λ) shape presents thickening characteristics but not gellingones.

The Iota (ι) carrageenans are, in the concept of the present invention,used on their own without the addition of another gelling agent,contrary to carrageenans used in the prior art of manufacturing filmsfor hard or soft capsules. The concentration in carrageenans willpreferably be higher than 5% of the medium with a maximum limit set to80%. Advantageously, the volume of dissolution of the carrageenans canbe water as well as a polyhydric alcohol blend of which the proportionin alcohol will vary between 0 and 60%.

The medium must be buffered so as to avoid a deterioration of thecarrageenans in time under the effect of heat. In effect, in buffermedium and during a twenty-four hour period, a diminution of theviscosity of the medium through progressive hydrolysis of thecarrageenans freeing acid radicals in the medium can be seen. Thisreaction is blocked when the medium is buffered. The pH value can varybetween 5 and 12. Different buffering systems can be used

citrates buffer: citric acid/citrates,

phosphates buffer: sodium phosphate or potassium phosphate,

phthalate buffer: potassium diphthalate/hydrochloric acid,

borate buffer: boric acid/ sodium borate,

carbonate buffer: bicarbonate/carbonate.

The agents favorising the dissolution of carrageenans belong to thealkaline class and the alkaline earth: sodium, calcium, potassium, etc,and are introduced in the medium in the shape of:

salts of hydrochloric, sulfuric, nitric, phosphoric, and citric acidsand derived acids;

hydroxides.

The proportion of alkaline ions and alkaline earths that can beintroduced in the medium varies between 0 and 50% in relation to thefinal volume of solution.

The elasticity of the films is obtained by the use of plasticizers whichbelong to the polyoxyls class: glycerol, sorbitol, maltodextrins,dextrose, mannitol, xylitol, polyoxyethylene glycol 400 to 6000, naturalglycerides and hemisynthetics and their derivatives, etc.

The quantity of these substances introduced in the solution ofcarrageenans is such that the coefficient of elasticity of the film canvary from 1 to 5 (1 to 5 times the initial length). The proportion ofthese substances that can be introduced in the medium varies between 0and 30% in relation to the final volume of the solution.

The obtaining of a gradual disintegration time defined from the film iscontrolled by the introduction of tensio-actives in the medium, combinedor not to substances presenting a power of disintegration. Thetensio-actives used in the present invention can be

non ionics. These are:

sorbitane esters: polysorbates, spans, tweens, etc.

fatty acids polyethoxyls: stearate of PEG 8 to stearate of PEG 100;

fatty polyethoxyled alcohols: blend of ethyl of monolaurate of PEGhaving from 4 to 23 oxyethylen groups on the polyoxyethylenic chain,etc.

glycol esters: stearate of methylglycol;

glycerol esters: monostearate of glycerol; etc.

esters of PEG;

saccharose esters;

ethyls of fatty alcohol and of PEG: Brij;

ethyls of alkyl phenol and of PEG;

tensio-actives presenting an amide function such as:

monoethanolamide of fatty acids of coprah, of lauric acid, etc.

diethanolamide of myristic acide, of lauric acid, etc.

mono-isopropanolamine of lauric acid.

ionics. Which are:

derived sulfates: the laurylsulfate of sodium and its derivatives;

derived sulfones dodecylsulfosuccinate of sodium and its derivatives;

quaternary ammoniums: cetyltrimethylammonium chloride, laurylpyridinium,distearyldimethylammonium, etc.

amphoterics: ammonium betaine of alkyldimethyl of coprah, derived fromamids of fatty acid with betainic structure, lauryl-b-iminodipropionicacid and its derivatives, lauryl-myristyl-b-aminopropionic acid and itsderivatives, etc.

The quantity of these substances introduced in the carrageenans solutionis such that the disintegration time can vary from 3 minutes to 8 hours.These quantities can vary from 0% to 20% in relation to the final volumeof solution. These tensio-actives can be combined with substances toimprove the disintegration time, like wheat, rice, corn, manioc starchwhether they have or not been subject to modifications. The quantitiesused can vary from 0 to 20% in relation to the final volume of solution.

Manufacturing additives such as preservatives, colourings and opaqueagents can be introduced in the carrageenans solution. The proportion ofpreservatives can vary from 0 to 10% in relation to the final volume ofsolution. Colourings can dissolve in water or can be fixed on a aluminelacquer or any other support. The optimum level required is situatedbetween 0.01 and 5% for colourings and from 0 to 10% for opaque agentsin relation to the final volume of solution.

Solution made this way present a viscosity comprised between 200 and1,000,0000 millipascals. From these solutions, films can be made whichrepresent, at the time of pouring, a thickness of about 0.5 to 4.0 mm.After drying, the films represent a thickness ranging between 0.2 and2.0 mm thick. Their retracting power after drying is situated between 0and 50%.

Films obtained in this way can be lubricated to ease theirimplementation at the level of machines to make gelled capsules or tomake soft capsules. The lubricants that can be used are:

classical edible oils (groundnut, sunflower, olive oils, etc.),

emulsifiers such as esther of glycerol and polyoxyethylene glycol,triglycerids, esters of propylene glycol and their derivatives.

These lubricants can be used pure or diluted with a dilution of 10 to75%.

Films obtained in this way for manufacturing whether it be gelledcapsules or soft capsules can contain powders, solutions and suspensionsof which the carriers are constituted by:

oils: groundnut oil, sunflower oil, olive oil, etc, and of the labrafiltype;

polyoxyethyleneglycol: PEG 400, 600 etc.

propylene glycols

emulsifiers polysorbates, soya lecithin;

suspension agents such as hydrogenated oils

aqueous solutions containing a quaternairy ammonium.

The present invention also concerns the manufacturing process of filmswith an adaptation for obtaining soft capsules. Made by heating, themanufacturing of these films comprises three stages, that is:

preparation of the solution buffer by different constituents:dissolution agents, plasticizers, tensio-actives, preservatives andcolourings;

the swelling of carrageenans in the basic solution;

and the dispersion if necessary of the opaque agent.

EXAMPLES

The following examples of embodiment are composition formulae given asnon limitative examples.

Example No 1

Example N^(o) 1 Carrageenans 15 g Sodium chloride 3 g glycerine 15 gWater 132 g Example N^(o) 2 Carrageenans 15.0 g Sodium hydroxide 1.8 gglycerine 7.5 g Water 140.7 g Example N^(o) 3 Carrageenans 15.00 gSodium hydroxide 1.80 g glycerine 7.50 g Orange-yellow S 0.0 g Water140.65 g Example N^(o) 4 Carrageenans 15.00 g Sodium hydroxide 1.80 gglycerine 7.50 g Polysorbate 80 1.50 g Example N^(o) 5 Carrageenans15.00 g Potassium chloride 2.00 g glycerine 7.50 g Polysorbate 80 1.50 gSodium methyl parahydroxybenzoate 0.12 g Sodium propylparahydroxybenzoate 0.03 g Water 139.05 g Example N^(o) 6 Carrageenans39.500 g Sodium chloride 1.918 g glycerine 6.000 g Polysorbate 80 6.000g Sodium methyl parahydroxybenzoate 0.360 g Sodium propylparahydroxybenzoate 0.090 g Monosodium dihydrogen phophate 0.390 gDisodium hydrogen phosphate 7.320 g Water 300.00 g

In a 500 litres stainless steel container with double walls, fitted withan agitation and vacuum system:

is introduced 300 kg of water, the sodium chloride, the monosodicphosphate, the disodic phosphate, the polysorbate 80, the glycerine andthe preservatives,

the vacuum is set up and the carrageenans are added with agitation withthe temperature being maintained between 90° C. and 100° C. (theagitation speed is in the order of 1200 to 5000 revolutions per minuteand preferably 2000 revolutions per minute),

and this agitation is maintained until a more or less viscous mass isobtained. It can be kept for more than twenty four hours at 90° C.

The carrageenans solution obtained in this way is then transferredtowards the machines for manufacturing gelled capsules or soft capsuleswhere the storing temperature is maintained between 80° C. and 90° C.

In the case of soft capsules, the film obtained is then dehydrated byfreezing at −4° C. during thirty minutes. Soft capsules are obtained inthis way by sealing the films after lubrification according to anadaptation of the SCHERER method, by heating the dies at a temperatureset between 70° C. and 100° C.

What is claimed is:
 1. A viscous aqueous composition for making soft orhard capsules for aqueous and oily solutions, the composition comprisingan aqueous medium and a single gelling agent consisting of an iotacarrageenan, the concentration of the iota carrageenan being at least 5%of the aqueous medium, the composition further comprising at least oneion selected from the group consisting of the alkaline and alkalineearth ions.
 2. A viscous aqueous composition according to claim 1, theconcentration of the iota carrageenan being from 5% to 80% of theaqueous medium.
 3. A viscous aqueous composition according to claim 1wherein the aqueous medium comprises a polyhydric alcohol.
 4. A viscousaqueous composition according to claim 1, wherein the composition isprepared by dissolving the iota carrageenan in an aqueous buffer medium.5. A viscous aqueous composition according to claim 1, wherein thecomposition is prepared by dissolving the iota carrageenan in an aqueousmedium having a pH of from 5 to
 12. 6. A viscous aqueous compositionaccording to claim 5 wherein the aqueous medium includes a buffer pairselected from the group consisting of citric acid/citrate, monosodiumdihydrogen phosphate/disodium monohydrogen phosphate, monopotassiumdihydrogen phosphate/dipostassium monohydrogen phosphate,bicarbonate/carbonate, potassium diphthalate/ hydrochloric acid, andboric acid/sodium borate.
 7. A viscous aqueous composition according toclaim 1 wherein the at least one ion selected from the group consistingof the alkaline and alkaline earth ions is selected from the groupconsisting of sodium, calcium and potassium ions.
 8. A viscous aqueouscomposition according to claim 1 wherein the at least one ion selectedfrom the group consisting of the alkaline and alkaline earth ions has aconcentration from 0% to 50% of the aqueous medium.
 9. A viscous aqueouscomposition according to claim 1 wherein the at least one ion selectedfrom the group consisting of the alkaline and alkaline earth ions isprovided by the corresponding compound selected from the groupconsisting of alkaline and alkaline earth hydroxides and alkaline andalkaline earth salts of hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, citric acid, and derivatives thereof.
 10. A viscousaqueous composition according to claim 1 further comprising aplasticizing agent selected from the group consisting of sorbitol,glycerine, mannitol, xylitol, lactitol, polyoxyethylene glycols andtheir derivatives, and semi-synthetic glycerides and their derivatives.11. A viscous aqueous composition according to claim 10 wherein theconcentration of the plasticizing agent is from 0% to 30% of the finalvolume of the composition.
 12. A viscous aqueous composition accordingto claim 1 further comprising a surfactant for controlling thedissolution of the soft or hard capsules, the surfactant being selectedfrom the group consisting of non-ionic surfactants, ionic surfactants,and amphoteric surfactants.
 13. A viscous aqueous composition accordingto claim 12 wherein the concentration of the surfactant is from 0% to20% of the final volume of the composition.
 14. A viscous aqueouscomposition according to claim 1 further including a disintegratingagent for controlling the dissolution of the hard or soft capsules, thedisintegrating agent being selected from the group consisting ofstarches and derivatives thereof.
 15. A viscous aqueous compositionaccording to claim 14 wherein the concentration of the disintegratingagent is from 0% to 20% of the final volume of the composition.
 16. Aviscous aqueous composition according to claim 15 wherein theconcentration of the colorants is from 0.01% to 5% of the final volumeof the composition.
 17. A viscous aqueous composition according to claim1 further comprising a preservative and colorants.
 18. A viscous aqueouscomposition according to claim 17 wherein the concentration of thepreservative is up to 10% of the final volume of the composition.
 19. Afilm formed from a viscous aqueous composition according to claim 1, thefilm further comprising a lubricant selected from the group consistingof oils, esters of glycerol, esters of polyoxyethylene glycol,triglycerides, esters of propylene glycol, and derivatives thereof. 20.A soft or hard capsule formed from a viscous aqueous compositionaccording to claim
 11. 21. A soft or hard capsule according to claim 20,the gel capsule being filled with an aqueous material or an oil.
 22. Aprocess for making soft or hard capsules from a viscous aqueouscomposition, the process comprising: (a) preparing a hydrocolloidalsolution by (1) dispersing iota carrageenan at elevated temperatureunder vacuum in an aqueous medium to provide a hydrocolloidal solution,the concentration of the iota carrageenan being at least 5% of theaqueous medium, the medium containing alkaline ions or alkaline earthions, a plasticzer, and a surfactant; and (2) maintaining the solutionbetween 50° C. and 90° C. during storage; (b) forming a film for hard orsoft capsules from the hydrocolloidal solution; (c) forming and sealingcapsules from the film, the sealing temperature of the capsules beingmaintained between 50° C. and 90° C. by means of preheated forming dies.23. A process according to claim 22, the process further comprisingtreating the film by dehydrating it to bring the residual moisture levelof the film to about 80% to 20% before forming and sealing the capsules.24. A process according to claim 22 wherein the film is dehydrated by aheating step selected from oven drying and exposure to microwaves.
 25. Aprocess according to claim 22 wherein the film is dehydrated byfreezing.